Hepatitis B virus (HBV) is a hepatotropic virus that can cause severe liver diseases including acute and chronic hepatitis and hepatocellular carcinoma (HCC). There are ~350 million people in the world that are chronically infected by this virus, resulting in 0.5-1 million deaths every year. HBV has a very narrow host range, which has greatly hampered its research. The development of several mouse models in recent years, however, has partially overcome this problem and generated many important findings for understanding HBV replication and pathogenesis. By crossing female hemizygous HBV transgenic mice to male nave mice, we were able to obtain non-transgenic mouse pups. When these non-transgenic mouse pups were injected with the HBV genomic DNA by hydrodynamic injection, the HBV replication persisted in the mouse liver for up to seven months, resembling the vertical transmission of HBV in patients. Clinically, over 90% of babies born to women who are HBV carriers will become HBV carriers. This vertical transmission is the most common way of HBV transmission, particularly in HBV endemic areas, and the most important reason for chronic HBV infection. Our mouse model thus provides us with a unique opportunity to study the mechanism of HBV persistence after vertical transmission. We will use this mouse model to investigate the role of the HBV e antigen (HBeAg), which is thought to play a very important role in establishing persistent infection after the vertical transmission, and a class of HBV mutants, which carry a double-nucleotide mutation in the basal core promoter (BCP) and have a reduced expression level of HBeAg, in HBV persistence and pathogenesis. In addition, our recent studies indicated that HBV persistence could also be affected by the size of viral inoculums and interferons and (IFN-/). Thus, we will also investigate the role of these factors in HBV persistence. Our proposed research will provide important information for us to understand HBV replication and persistence and facilitate the development of treatments for HBV patients.